REGULATORY RECOGNITION OF SECONDARY WORKING STANDARDS
(1) Human Drug CGMP Notes, Vol 9, Number 3, 2001 (Internal FDA Publication):
Q: Can a company use reference standards from sources other than the USP?
A: Yes. Using a source other than USP can be acceptable provided the reference standard incorporates the critical characteristic properties, is suitable for the intended purpose, and is supported by complete documentation…..The supplier’s certificate of analysis should report the results of testing to adequately characterize the material across a complete range of quality characteristics.
(2) FDA: Guidance for Industry; Analytical Procedures and Methods Validation, August 2000:
“A reference standard (i.e., primary standard) may be obtained from the USP/NF or other official sources (e.g., CBER, 21 CFR 610.0). A working standard (i.e., in-house or secondary standard) is a standard that is qualified against and used instead of the reference standard.”
(3) European Pharmacopoeia, Chapter 5.12:
“Secondary standard: A standard established by comparison with a primary standard. A secondary standard may be used for routine quality control purposes for any of the uses described above for primary standards provided that it is established with reference to the primary standard.”
Qualification of Pharmaceutical Working Standards
The certified standard is very much important in pharmaceutical analysis. It ensures that the performed analysis is accurate and assures the safety of the drug product. The analysis is always carried out by using the working standard and results are reported against the working standard.
What is Working Standard?
A working standard is defined as, “A drug substance of established quality and purity as shown by comparison to the reference standards.” This working standard is used for routine analysis.
The working standard is qualified against the pharmacopeial reference standard or certified reference standard. Qualification of a working standard is done by using a verified or validated analytical method and its results are compared with the reference standard.
Why Use Working Standard?
Primary Standards, Reference Standards, or Pharmacopeial Standards is well characterized and certified materials by standard regulatory agencies or appropriate laboratories. These reference standards are available with minimum pack quantity at a high cost. Due to the higher cost of the primary reference standard, it is not possible to use this standard for routine analysis. Due to this reason, the working standard is prepared for routine analysis. bearing reference to the original certified reference material.
Selection of Drug Substance:
The working standard must be high-purity grade materials. Following are the selection criteria of the drug substance batch for the working standard preparation.
- Select the drug substance lot recently manufactured with an adequate validity period i.e. essential retest period or with a suitable expiry date.
- Availability of drug substance with valid COA and must comfortably comply with the assigned specification.
- Analyze 3 different batches of drug substances with the verified or validated test procedure.
- All three batches must comply with assigned in-house or pharmacopeial specifications.
- Select the single batch of drug substance that must be available in sufficient quantity.
- The selected batch sample must comply with all test specifications comfortably and the assay value close to 100 %.
- Select the batch number for the working standard preparation and collect a sufficient amount of sample quantity for analysis as well as for use as a working standard. Different vials with a minimum quantity will be sufficient for 1 month. This quantity and number of vials again depend on the requirement of standard per analysis, nature of the drug substance, and stability of the drug substance.
- The batch selected for working standard preparation must be analyzed in triplicate.
Qualification of Working Standard:
- The use of primary reference standards for the working standard qualification must have characterization data with valid COA or a valid lot of pharmacopeial reference standards.
- Analysis of working standards should be carried out by using calibrated instruments.
- The selected drug substance shall be tested as per standard test specifications and standard test procedure of IP/ BP/EP/JP/USP or in-house criteria against the pharmacopeial reference standard or primary reference standards.
- Mainly following tests shall be performed for the preparation of the working standard:
- Identification: By HPLC, TLC, IR, UV-VIS Spectrophotometer, and Chemical methods,
- Loss of drying / Water content,
- Related substances: By TLC, GC, HPLC,
- Residual solvent analysis by HSGC,
- Assay: By HPLC, UV-VIS Spectrophotometer, and Chemical methods. The assay performed in triplicate should not deviate ± 2 % and it should be within specification.
- There should not be any deviation, errors, or out-of-specification results at the time of analysis.
- If the assay is found more than 100 % then consider it as 100 %.
Assign the purity on an as-is basis and also need to check if there is any salt and base correction factor required. Also, it must have clear instructions on the vial about using purity on an as-is basis or dry the standard before use with clear temperature conditions or depending on the pharmacopeial monograph or as per primary standard test procedure.
After analysis assigns the validity depends upon the nature and stability of the drug substance. The validity of the working standard shall be assigned for 1 year or it must be within the retest date or expiry date of the drug substance assigned by the manufacturer.
After completion of the analysis and report generated, prepare the COA, and submit it for the QA review along with a hard copy or electronic data.
Storage of Working Standard:
After approval of the report label the working standards bottles properly with the following details:
- Name of the compound,
- Physical Description,
- LOD/water content result,
- Assay or Purity on an as-is basis, (Must have clear instruction on the vial about Using purity on an as-is basis or Dry before use with clear temperature conditions)
- Vial number,
- Date of preparation,
- The validity or Retest date,
- Storage Condition.
Store the working standard as per the storage condition of the drug substance. The validity of working standards shall be one year or depend on the nature and stability of the compound. Working standards shall be stored in amber-colored glass bottles with airtight closures. Each vial shall be used for a maximum of 2 months or depending on the nature of the standard.
One vial with an adequate quantity of the working standard shall be kept as a “Control sample”.
The working standards shall be revalidated at well-defined intervals to ensure their purity, integrity, and authenticity. Maintain the usage record of the working standard.
To ascertain the degree to which an analytical method is deemed suitable for its intended use, the validation parameters set forth in ICH Q2(R1) Validation of Analytical Procedures (6) stipulate the following criteria:
- Specificity—evaluation of interference from extraneous components.
- Linearity—linear range of the method.
- Range—the interval between the lower and upper concentration amounts of analyte in the sample.
- Accuracy—a measure of the closeness of agreement between the value obtained and the theoretical.
- Precision—a measure of the closeness of agreement (degree of scatter) of the data values over a number of measurements (i.e., injection repeatability, analysis repeatability (multiple measurements, same analyst) and intermediate precision (multiple measurements, different days, different analysts), reproducibility (precision between different labs).
- Detection limit—the lowest level at the analyte can be detected.
- Quantitation limit—the lowest level at the analyte can be quantitated.
- Robustness—effects of small changes in method parameters.
- System suitability testing—evaluation of the suitability of the equipment.
Expired working or reference standards should not be used. Instead, they should be discarded immediately in a proper way.